Mouse IL-2/CD25 fusion protein induces regulatory T cell expansion and immune suppression in preclinical models of systemic lupus erythematosus

Jenny H. Xie, Yifan Zhang, Martine Loubeau, Paul Mangan, Elizabeth Heimrich, Christian Tovar, Xiadi Zhou, Priyanka Madia, Michael Doyle, Shailesh Dudhgaonkar, Anjuman Rudra, Siva Subramani, James Young, Luisa Salter-Cid, Thomas R. Malek, Mary Struthers

Research output: Contribution to journalArticlepeer-review

Abstract

Systemic lupus erythematosus (SLE) is associated with an IL-2-deficient state, with regulatory T cells (Tregs) showing diminished immune regulatory capacity. A low dose of IL-2 has shown encouraging clinical benefits in SLE patients; however, its clinical utility is limited because of the requirement of daily injections and the observation of increase in proinflammatory cytokines and in non-Tregs. We recently showed that a fusion protein of mouse IL-2 and mouse IL-2Rα (CD25), joined by a noncleavable linker, was effective in treating diabetes in NOD mice by selectively inducing Treg expansion. In this report, we show that mouse IL-2 (mIL-2)/CD25 at doses up to 0.5 mg/kg twice a week induced a robust Treg expansion without showing signs of increase in the numbers of NK, CD4+Foxp3-, or CD8+ T cells or significant increase in proinflammatory cytokines. In both NZB × NZW and MRL/lpr mice, mIL-2/CD25 at 0.2-0.4 mg/kg twice a week demonstrated efficacy in inducing Treg expansion, CD25 upregulation, and inhibiting lupus nephritis based on the levels of proteinuria, autoantibody titers, and kidney histology scores. mIL-2/CD25 was effective even when treatment was initiated at the time when NZB - NZW mice already showed signs of advanced disease. Furthermore, we show coadministration of prednisolone, which SLE patients commonly take, did not interfere with the ability of mIL-2/CD25 to expand Tregs. The prednisolone and mIL-2/CD25 combination treatment results in improvements in most of the efficacy readouts relative to either monotherapy alone. Taken together, our results support further evaluation of IL-2/CD25 in the clinic for treating immune-mediated diseases such as SLE.

Original languageEnglish (US)
Pages (from-to)34-43
Number of pages10
JournalJournal of Immunology
Volume207
Issue number1
DOIs
StatePublished - Jul 1 2021

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Fingerprint

Dive into the research topics of 'Mouse IL-2/CD25 fusion protein induces regulatory T cell expansion and immune suppression in preclinical models of systemic lupus erythematosus'. Together they form a unique fingerprint.

Cite this